ABSTRACT Intracerebral hemorrhage (ICH) is a devastating form of cerebrovascular disease with no FDA- approved treatments. It is generally accepted that ICH-induced neuroinflammatory responses mediate development of cerebral edema, intracranial hypertension, and secondary neuronal injury. One promising strategy for ICH neuroinflammatory modulation is through the downstream effects of apolipoprotein E (apoE). Previous studies from our lab and others have demonstrated that endogenous apoE modifies neuroinflammatory responses by downregulating glial activation and release of pro-inflammatory mediators making it a compelling target for therapeutic development. However, the therapeutic potential of the intact apoE protein is limited, as it does not cross the blood-brain barrier. To address this limitation AegisCN developed CN-105, a 5-amino acid peptide that mimics the polar face of the apoE helical domain involved in receptor interactions. In well-established preclinical models of ICH, CN-105 improves short- and long-term neurobehavioral and histological outcomes, decreases cerebral edema, and increases neuronal survival. Our preclinical work with CN-105 has led to the successful completion of an IND and translation to early clinical studies. CN-105 demonstrated an excellent clinical safety profile in Phase 1 healthy volunteer single and multiple dose escalation safety and PK studies and, as recommended by the FDA, we have initiated a multisite open label safety study in patients with ICH. CN-105's efficacy in preclinical ICH models is firmly established, as are its neurorestorative and anti-inflammatory effects in other preclinical models of acute brain injury. However, this knowledge alone is insufficient for therapeutic translation. To bridge this gap, the objective of this application is to define the effects of gender, age, and chronic hypertension on long-term neurobehavioral outcomes in preclinical ICH-relevant paradigms and to identify surrogate imaging and biochemical markers of CN-105 target engagement and efficacy. We will complete the following milestones: 1: Establish a greater than 20% treatment effect of CN-105- vs. vehicle-treatment on vestibulomotor deficit (rotorod latency) at Day 7 in a rat model of ICH with comorbid hypertension; 2: Establish treatment effects on vestibulomotor function as a function of age and gender to inform clinical translation. Completion of these milestones will facilitate translation into an adaptive randomized clinical trial for patients with acute ICH through Phase 2 STTR funding.